Vitamin E is commonly found in vegetation and more abundantly in seeds from which tocopherols, in the natural state, are easily absorbed and utilized in humans and animals, wild and domestic. Processing of foods and feeds by industry for long term storage promotes accelerated degradation of Vitamin E content. To compensate for the loss of natural Vitamin E from food sources, nutritional supplements of natural or synthetic Vitamin E are administered by injection or orally. It is well known that tocopherols are unstable molecules. To improve tocopherol stability, manufacturing processes generally attach an acetate or succinate group to tocopherol, making Vitamin E acetate or succinate (d- or dl-alpha-tocopheryl acetate or succinate). These modifications may decrease the bioavailability of tocopherol and create a need for a more readily bioavailable Vitamin E. In some species both the alpha-tocopherol and alpha-tocopheryl acetate even in water dispersible forms are not bioavailable. Patton in "Feedstuffs", Apr. 24, 1989, p. 69, reported that in zoo animals dosed with dl-alpha-tocopheryl acetate, one-half of the administered tocopherol was absorbed, the remaining being excreted unchanged.
Enhanced absorption of Vitamin E acetate (VEA) has been studied previously by using aqueous dispersions and solubilized preparations. Several studies suggest that in the intestine, absorption of Vitamin E is influenced by presence of certain dietary lipids and the hydrophilic nature of the dosage form. Gallo-Torres (In Vitamin E. A Comprehensive Treatise; Machlin, L. J., Ed.; Marcel Dekker: New York, 1980; Vol. 1, p. 182) cited a report showing enhanced absorption of tocopherol by solubilizing tocopherol in medium-chain triglycerides. The work of Schnandke and Schmidt, described by Gallos-Torres (In Vitamin E, A Comprehensive Treatise, supra, p. 181) showed that a VEA in a 3% aqueous solution of Tween-80 was absorbed at twice the rate of a vegetable oil solution of VEA. In a study by Kimura et al. (Chem. Pharm. Bull., 37(2), pp. 439-441) enhanced absorption of tocopherol in rats was promoted by an aqueous lecithin dispersed Vitamin E acetate containing medium chain triglycerides. While these reports showed that aqueous dispersions enhance Vitamin E absorption in some species, it has been discovered that elephants and black rhinoceros do not absorb some water dispersible forms well. These works also show that one cannot assume that water dispersible VEA of natural or synthetic origin will be readily bioavailable. However, these works have demonstrated that enhanced absorption of Vitamin E was promoted by solubilized Vitamin E and aqueous dispersions of Vitamin E.
It is well known that the efficacy of the hydrophilic nature of aqueous Vitamin E solutions and dispersions upon enteral absorption of Vitamin E can be demonstrated by increased absorption of hydrophilic Vitamin E by the normal and compromised intestine. It is known in the art that the source of Vitamin E, natural or synthetic, also affects its bioavailability. In the compromised gut, Vitamin E absorption was studied in patients with lipid malabsorption syndromes such as cholestatic liver, and cystic fibrosis. Such patients are unable to absorb Vitamin E or other dietary lipids. When a water soluble form of Vitamin E (d-alpha-tocopheryl polyethylene glycol 1000 succinate, or "TPGS") was administered orally to such patients, an elevation of blood tocopherol was detected within one week. When the same patients were dosed with tocopherol in vegetable oil, there was no significant increase of tocopherol in the blood, (Traber M. G., Thellman, C. A., Rindler, M. J., Herbert, J. K., Am. J. Clin. Nutr., 1988, 48, 605-611). Thus, the type of tocopherol, natural or synthetic, and the hydrophilic nature of TPGS can be important in determining the absorption and bioavailability of Vitamin E in humans and animals.
A human clinical trial conducted by the National [Research Council of Canada and animal trials of Hidiroglou et al. (J. Animal Sci., 1988, 66:3227 3234) studied the relative bioavailability of natural and synthetic Vitamin E and both concluded that the natural Vitamin E has a bioavailability higher than previously thought.
The advantage of administering Vitamin E in a water-dispersible formulation was shown by Bateman et al. (J. Pharm. Pharmacol., 1984, 37(7), 461-464) in a human clinical study in which Vitamins A, E, and B.sub.2 were formulated into a liquid vehicle (Aqua Biosorb) and encapsulated into soft gelatin capsules which were given orally. In the formulation, B.sub.2 was incorporated into the formulation as a suspension with a particle diameter of .ltoreq.100 nm. The soft elastic gelatin capsules contained by weight % 20% polysorbate 80, 1% sorbitan monooleate and 79% distilled monoglyceride as the water dispersible base. Bateman demonstrated that the hydrophilic nature of water soluble Vitamin B.sub.2, in addition to the lipid soluble Vitamins A and E in his dosage formulation, showed enhanced absorption.
Brooks describes in U.S. Pat. No. 3,253,992 the composition of anhydrous water dispersible fat soluble vitamin preparations and aqueous dispersions of these preparations. The Brooks patent requires only poly-oxyethylene sorbitan monooleate and a distilled monoglyceride derived from safflower oil (Myverol 18-98) as the emulsifier and lipid soluble vitamins. The Brooks patent does not address the use of monoglyceride blends or the use of TPGS, a potent biologically active tocopherol, as an emulsifier. We have discovered that such aqueous dispersions have limited stability in vitro.
Stillman in U.S. Pat. No. 4,551,332 teaches the use of frozen solutions of Vitamin E blends comprised of glyceryl mono- and distearate and in some cases Jojoba oil for dermatological and cosmetic applications. Dispersibility in aqueous systems and oral use for humans and animals are not addressed.
With the exception of the Stillman patent, all other prior art cited above discussed lipid soluble nutrients which were administered as an aqueous dispersion. Other literature disclosed the use of TPGS as a solution. Heretofore, nothing exists in the prior art which teaches delivery of Vitamin E in a substantially anhydrous vehicle which is a free-flowing solid and readily dispersed in aqueous media in vivo to provide enhanced enteral bioabsorption.